Ovarian cancer is the leading cause of death from gynecologic malignancy among women in the United States, and at most ages is responsible for more deaths than all other gynecologic cancers combined (Cramer, D., "Epidemiology of Gynecologic Cancer", p. 80, in Gynecologic Oncology, 2d ed., (R. C. Knapp and R. S. Berkowitz, eds.), McGraw Hill, New York, 1993)). Annual U.S. incidence and mortality are 26,600 and 14,800, respectively (Silverberg, CA: A cancer journal for physicians 44:4-8 (1994)). The age specific incidence rises sharply after 50 years of age (Cramer, D., p. 80 of Gynecologic Oncology, 2d ed., (R. C. Knapp and R. S. Berkowitz, eds.), McGraw Hill, New York, 1993)). More than 70% of cases present in late state (Piver, M. S. et al., "Ovarian Cancer", p. 253, in Gynecologic Oncology, 2d ed., (R. C. Knapp and R. S. Berkowitz, eds.), McGraw Hill, New York, 1993)) and consequently have poor prognosis. In such cases most women die of the disease. Therapeutic advances have had negligible impact on the overall survival rate during the past thirty years. However, if cancer is detected in early stage before dissemination of the disease, the five year survival rate is over 90% (Yound, R. C. et al., N. Engl. J. Med. 322:1070-1073 (1990)). Furthermore, recent genetic research on ovarian cancer provides evidence of a unifocal origin (Mok, C. H. et al., Cancer Research 52:5119-5122 (1992)). These observations make early detection of ovarian cancer through a mass screening program of postmenopausal woman an attractive method for reducing mortality due to ovarian cancer.
Invasive surgery is the only definitive method of diagnosis for ovarian cancer. Nevertheless, most epithelial ovarian malignancies shed an antigenic determinant into the blood that is detectable using the CA125 radioimmunoassay (RIA) (Bast, R. C. Jr. et al., N. Engl. J. Med 309:883-887 (1983); Klug, T. L. et al., Cancer Res. 44:883-887 (1984)). In normal populations, CA125 levels are rarely elevated (Jacobs, I. et at., submitted 1992; Zurawski, V. R. Jr., Obstet Gynecol. 69:606-611 (1987)); however CA 125 levels have been elevated prior to clinical detection of ovarian cancer (Bast, R. C. Jr. et al., Gynecol. Oncol. 22:115-120 (1984); Zurawski, V. R. Jr., Int. J. Cancer 42: 677-680 (1988)). CA125 levels correlate with tumor volume (Zurawski, V. R. et al., Gynecol. Oncol. 30:7-14 (1988)). Progressively higher levels of CA125 are associated with more advanced disease, and subsequent lower levels with absence of the disease post-operatively. A level of 35 U/ml CA125 has been used to evaluate patients with demonstrable cancer (Bast, R. C. Jr. et al., Engl. J. Med. 309:169-171 (1983)). Levels of 30 U/ml to 35 U/ml have been used in retrospective and prospective studies of the incidence of ovarian cancer (Zurawski, V. R. Jr. et al. Gynecol. Oncol 36:299-305 (1990); Einhorn, N. et al., Obstet. Gynecol. 80:14-18 (1992)). Due to the low rate of occurrence of ovarian cancer, the positive predictive value of these CA125 reference levels for the presence of ovarian cancer are less than 2%. However, a high positive predictive value is necessary for an early detection program of ovarian cancer, because of the invasive nature of the surgery necessary for biopsy or removal of an ovary. Literature has suggested a minimum required positive predictive value of 10% (Jacobs, I. and Best, R., Human Reproduction, 4:1-12 (1989)). Thus, early detection of ovarian cancer with the CA125 assay has been criticized as ineffective. A need remains for an effective method for evaluating individuals at risk for ovarian cancer, in order to detect the disease in its early stages and reduce the rate of mortality due to ovarian cancer.